Background: Literature currently supports the limited use of prophylactic antibiotics within the trauma population. However, data supporting limited (≤24 h) or extended (>24 h) use in penetrating aerodigestive neck injuries is lacking. We sought to describe the role of prophylactic antibiotics in this population and hypothesized there was no reduction in complications for patients on extended prophylactic antibiotics. Methods: Using a single-center trauma registry, patients with penetrating aerodigestive neck injuries were identified over a 5-year period. Demographics, injuries, management, and prophylactic antibiotic utilization were collected. Patients were stratified by the utilization of extended prophylactic antibiotics. Outcomes included infection, leak, reinterventions, and mortality. Results: Of 436 patients with penetrating neck injuries, 72 (17%) patients were identified with aerodigestive injuries. Forty-one (57%) patients received extended (>24 h) prophylactic antibiotics, whereas 31 (43%) received limited (≤24 h) prophylactic antibiotics. There was no difference in the patient demographics or injury severity score between the two groups. Extended prophylactic antibiotic use was associated with higher rates of infection (22% vs. 3%, p = 0.036) and leak (15% vs. 0%, p = 0.034) and no difference in reintervention (20% vs. 3%, p = 0.068) or mortality (10% vs. 13%, p = 0.719) compared with limited prophylactic antibiotics. Median duration of extended antibiotic use was 7 days. Operative intervention was equivalent across extended prophylactic antibiotics and limited antibiotics groups (59% vs. 58%, p = 0.968). Conclusions: There is insufficient evidence to support the extended (>24 h) use of prophylactic antibiotics in patients with penetrating neck aerodigestive injuries.